Substituted bis



United States Patent 3,072,671 SUBSTITUTED BIS(4-THIAZOLIDIN ONES) AND PROCESS THEREFOR Gerhard Satzinger, Memingen, Allgau, Germany, as-

siguor to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware N Drawing. Filed Mar. 6, 1961, Ser. No. 93,363 9 Claims. (Cl. 260-306.7)

The present invention relates to new and novel bis(4- thiazolidinones) of the formula:

wherein R is hydrogen, lower alkyl or aryl; R is lower alkyl; R is hydrogen or lower alkyl; and A is an alklylene radical having 1 to 6 carbon atoms, -CHz('3H-R in which R; is an alkylene radical of 1 to 4 carbon atoms, or

in which a and b are 1 to 3 and R is a lower alkyl group. The present invention also relates to a method of preparing these substituted bis(4-thiazolidinones).

The term lower alkyl as used in the specification and in the claims refers to branched and straight chain aliphatic groups having 1 to 6 carbon atoms.

The substituted bis(4-thiazolidinones) of this invention have been found to have interesting pharmacological activity as analgesics, sedatives and choleretic agents. In use, they may be formulated with conventional pharmaceutical carriers to form such typical dosage units as tablets, capsules, solutions, suspensions, suppositories and the like.

It has now been found that the new and novel substituted bis(4-thiazolidinones) of this invention may be prepared by the reaction of a substituted 4-thiazolidinone of the formula:

in which Y is halogen, for example chlorine, bromine or iodine, and B is an alkylene radical having 1 to 6 carbon atoms or a radical of the formula a, b, R, and R being as described hereinabove.

The product of the reaction is a compound formed of may be prepared as described in my application entitled in 300 ml. absolute ethanol.

the reactant with the substituted 4'-thiazolidinone start-' ing material material is a compound of the formula Y-B-Y, the linkage joining the two nuclei is an alkylene radical having 1 to 6 carbon atoms or a radical of the formula n)s --(UHz)b s where the reactant is a compound of the formula CH:CHR4Y 0 the linkage joining the two nuclei is a radical of the formula 0Hl-oH-R4- The reaction is carried out under anhydrous conditions by heating the reactants in an appropriate inert solvent such as methanol, ethanol, dimethylformamide and the like to a temperature of about 50 to about C. The reaction time is normally about one-half to about three hours. For optimum yields, the reactants should be present in the molar proportions of 2 parts of the substituted 4-thiazolidinone to 1 part of the reactant of the formula Y-BY or CH5CHR Y -At the conclusion of the reaction, the product is recov- Substituted 4-Thiazolidinones and Process Therefor" (Case A), filed concurrently herewith, now application Serial No. 93,301 filed March 6, 1961, by the reaction of a nitrile of the formula: v

with a mercapto ester of the formula:

alcohol having 1 to 6 carbon atoms and an alkali metaL' The following examples are included in order further to illustrate the present invention:

EXAMPLE I 3,3-(Z-Hydroxytrimethyleh) bis(2-Carbethoxymethylene-4-Thiaz0lidirt0ne A mixture of 37 g. (0.2 mole) Z-carbethoxymethylene-4-thiazolidinone and 9.2 g. (0.1) mole epichlorohydrin is added to a solution-of 4.6 g. (0.2 mole) sodium The mixture is heated under reflux for one-half hour and then cooled to room temperature. Dilution with an equal volume of water results in the precipitation of light yellow crystals which are treated with 1N NaOH, filtered and washed with wa,t e r. Recrystallization from dioxane/water yields 17 Patented Jan. 8, 1963 3 g. (40%) of 3,3'-(Z-hydroxytrimethylene)bis(Z-carhethoxymethylene-4-thiazolidinone, melting point 197 C.

Analysis.-Calc.: C, 47.43; H, 5.16; N, 6.51; S, 14.89. Found; C, 47.43.; H, 5.30; N, 6.52; S, 14.91.

EXAMPLE H 3,3'-Ethylenebis(Z-Carbethoxymethylenel- Thiazolidinone) To a stirred solution of 20.9 g. (0.1 mole) of the sodium salt of 2-carbethoxymethylene-4-thiazolidinone in 150 ml. of dimethylformamide are added 9.4 g. (0.05 mole) ethylene dibromide. The reaction mixture is heated to a temperature of 80 C. for one-half hour and is then cooled to room temperature. The cooled solution is filtered and evaporated to dryness and the residue is crystallized from dimethylformamide to yield 12.4 g. (62%) of 3,3'-ethylenebis(2-carbethoxymethylene-4-thiaz 'olidinone) as yellow crystals,'melting point 266 C.

Analysis.-Calc.: C, 47.98; H, 5.04; N, 6.99; S, 16.01. Found: C, 48.21; H, 5.16; N, 7.39; S, 15.56.

EXAMPLE III 3,3'-[ (M ethylimino) diethylene]Bis(2-Carbethoxymethylene-4-Thiaz0lidin0ne) To astirred freshly prepared solution of 0.1 mole di- (fi-chloroethynmethylamine in absolute ethanol (prepared by adding 19.1 g. of the amino hydrochloride to a solution of 2.3 g. sodium in 100 ml. absolute ethanol) is added a solution of 42 g. (0.2 mole) of the sodium salt of 2-carbethoxymethylene-4-thiazolidinone in 300 ml. absolute ethanol. The mixture is heated under reflux for 2 hours and is filtered to remove the sodium chloride. Upon cooling to -10 C., 25 g. (50%) of 3,3 [(methylimino)diethylene]bis(2 carbethoxymethylene-4-thiazolidinone) separates. This is then dissolved in 700 ml. ethyl acetate-and saturated with hydrogen chloride. Crystallization from 80% dioxane yields colorless crystals of the pure hydrochloride salt, melting point 225 C.

Analysis (of the hydrchl0ride).-Calc.: C, 46.19; H, 5.71; N, 8.51; S, 12.98; Cl, 7.18. Found: C, 44.71; H, 5.44; N, 8.59; S, 12.80; Cl, 7.21.

By procedures such as those set forth in the foregoing examples, other substituted bis (4-thiaz olidinones) may beprepa red, for example 3,3'(2-hydroxytrimethylene) bis( 2 'carbethoxymethylene-5-methyl-4-thiazolidinone), 3,3 (2 hydroxytrimethylene)bis[2 (a carbethoxybenzylidene) 4 thiazolidinone], 3,3'-trirnethylenebis(2- carbethoxymethylene-5-ethyl-4-thiazolidinone)', 3,3-trimethylenebis[2 (a carbethoxybenzylidene)-4-thiazolidinone], 3,3 [(methylimino)diethylene1bis[Z-(nt-carbethoxybenzylidene) 5 methyl-4-thiazolidone], 3,3- [(methylimino)diethylene]bis[2 (1 carbethoxyethylidene)-5-methyl-4-thia2olidinone] and the like.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing, from the spirit of my invention.

Having described my invention, what I desire tosecure by Letters Patent is:

1. A compound of the formula:

wherein R is a member selected from the group consisting of hydrogen, phenyl and lower alkyl; R is lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; and A is a bridging member selected from the group consisting of those of the formula --(CH where n is 1 to 6,

'CHr-?H(CH1)a where n is 1 to 4 and,

wherein a and b are 1 to 3 and R is a lower alkyl group.

2. 3,3 (2 hydroxytrimethylene)bis(2 carbethoxymethylene-4thiazolidinone) 3. 3,3 ethylenebis(2 carbethoxymethylene-4-thiazolidinone) 4. 3,3 [(methylimino)diethylene]bis(2 carbethoxymethylene-4-thiazolidinone) 5. 3,3 [(methylimino)diethylene]bis(Z-carbethoxymethylene-4-thiazolidinone) hydrochloride.

6. A method of preparing a compound of the formula:

wherein R is a member selected from the group consisting of hydrogen, phenyl and lower alkyl; R is lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; and A is a bridging member'selected from 'the group consisting of those of the formula CH where n is 1 to 6,

--CHg-(iJH(CH2)n' where n is 1 to 4, and

H1) r- I (CH2) 1- wherein a and b are 1 to 3 and R is a lower alkyl group, which comprises heating to a temperature of about 50 C. to about C. a mixture of a compound of the formula:

wherein M is an alkali metal and a member selected from the group consisting of Y-B-Y and CH:CH-R4-Y wherein R is an alkylene radical of l to 4 carbon atoms, Y is halogen, B is a bridging member selected from the group consisting of those of the formula (CH where n is 1 to 6, and

"' (CH2) r (CHI) irwherein a and b are 1 to 3 and R is a lower alkyl group, and R is an alkylene radical having 1 to 4 carbon atoms.

7. A method of preparing 3,3'-(2-hydroxytrimethylene) bis(2-carbethoxymethylene-4-thiazolidinone) which com prises refluxing an ethanol solution of Z-carbethoxymeth- 5 ylene-4-thiazolidinone and about one-half a molar equivalent of epichlorohydrin.

8. A method of prepar ng 3,3-ethylenebis (2-carbethoxymethylene-4-thiazolidinone) which comprises 6 9. A method of preparing 3,3'-[(methy1imino)diethyl eneJbis (Z-carbethoxymethylene-4-thiazolidinone) which comprises refluxing an ethanol solution of 2-carbethoxymethylene-4-thiazo1idinone and about one-half a molar heating to about 80 C. a dimethylformamide solution 5 equivalent of di-(fi-chloroethyl)-methylamine.

of 2-carbethoxymethylene-4-thiazo1idinone and about one-half a molar equivalent of ethylene dioromide.

N 0 references cited. 

1. A COMPOUND OF THE FORMULA: 